The conversion of a carbon-carbon double bond to a cyclopropane ring is a chemical transformation used commonly in the synthesis of organic chemical compounds. Cyclopropanation on a laboratory scale is commonly performed with the aid of a diazo compound, for example, diazomethane (DAM), and transition metal catalyst typically comprising a copper or palladium complex. Diazo compounds such as DAM are prepared from an N-alkyl-N-nitroso compound, more particularly a N-methyl-N-nitroso compound (MNC), and still more particularly with an MNC having the general formula R(N(NO)Me)x. In order to make such a process useful in industry, it would be highly desirable if both the MNC and the DAM could be formed in-situ, and further reacted without isolation, in order to avoid the hazards associated with handling these toxic materials. Such a process is described in WO 2015059290, wherein an N-alkyl-N-nitroso compound is generated in a liquid phase from a mixture of an amine HNRR′, water, NaNO2 and an acid. An organic solvent can be added to the N-alkyl-N-nitroso compound once it is formed to facilitate phase separation. The N-alkyl-N-nitroso compound partitions into the organic solvent provided for that purpose. A biphasic mixture is formed, and the organic phase can be separated from the aqueous phase in a phase separation step. Thereafter, the organic phase containing the N-alkyl-N-nitroso compound is added to an alkene substrate, without having first to isolate it in pure form. As the N-alkyl-N-nitroso compound is in an organic solvent, it can be cleanly and simply transferred into a reaction vessel containing an alkene substrate.
A particularly suitable N-alkyl-N-nitroso compound is N-nitroso-β-methylaminoisobutyl methyl ketone NMK (sometimes referred to as “Liquizald”) which can be prepared from the methylamine mesityloxide adduct through nitrosation in the presence of an acid.

NMK was first prepared by E. C. S. Jones and J. Kenner (JCS 363, 1933) and used for the preparation of diazomethane in the presence of base. Nitrosation (with 2 mol eq NaNO2) was carried out in the presence of HCl (>1 mol eq) and NMK was distilled after extraction from the organic phase. Decomposition of NMK in the presence of base gave DAM which was distilled before being used for the methylenation of benzoic acid.
NMK was also prepared by nitrosation of the methylamine mesityloxide adduct by using 2.5 mol-eq acetic acid and NaNO2 (2.35 mol-eq) in aqueous phase. Treatment of the crude NMK with base gave DAM, which was, once again, distilled before being used for the methylation of an acid (D. W. Adamson, J. Kenner JCS 1553 (1937).
The same method was later on used by C. E. Redemann, F. O. Rice, R. Roberts and H. P. Ward (Org. Synth. Coll. Vol. 3, 244, 1955) employing less acetic acid (HOAc) (1.7 mol-eq) and NaNO2 (1.2 mol-eq) per mol mesityl oxide for the preparation of NMK. The crude NMK was treated with base and DAM was distilled. References for further derivatization of DAM were given, however, the transition metal catalyzed methylenation of double bonds with DAM was unknown at that time.
From these prior art references one can conclude that although NMK and DAM can be efficiently generated from the methylamine mesityloxide adduct by nitrosation in the presence of acetic acid, the NMK and/or DAM were purified and isolated by distillation before being used in any subsequent reactions. Indeed, distillation was deemed necessary to separate NMK and/or DAM from acetic acid as methylation of acetic acid would occur as soon as DAM is generated. In other words, acetic acid is a competitive substrate in any methylation reaction and would thus decrease the yield of any desired methylenated product. The reaction of DAM with acetic acid is well documented in the art, see for example WO 0147869.
The transition metal catalyzed methylenation of alkenes with diazomethane formed from NMK has been described in WO 2013110932. In this reference, NMK is formed by the nitrosation of methylamine mesityl oxide adduct, in the presence of a tribasic acid, notably H3PO4. The tribasic acid is compared favourably over acetic acid because it reduces or even eliminates acid contamination in the NMK. After phase separation of the organic NMK phase, this procedure produces a 60-80% aqueous H3PO4 waste solution, and it is emphasized that phase separation is improved by the fact that sodium phosphate salts produced as a by-product of the reaction are close to saturation in the aqueous phase, and that the high level of salt saturation reduces the solubility of NMK in the aqueous phase, ensuring high yields and clean separation of NMK. It is emphasized that the use of the tribasic acid results in a cheaper process and a cleaner (less acidified) product than could be produced using prior art methods. In fact, comparative experiments in WO 2013110932 show that whereas the yields of NMK are similar whether one uses the tribasic acid H3PO4 or the mono-basic acetic acid, in the latter case the NMK product is contaminated by significant amounts of HOAc (6.4% w/w), which would indicate that using the NMK to subsequently generate DAM in order to methylate a substrate would not be appropriate without first purifying the NMK by distillation.
The use of the method described in WO 2013110932, e.g. preparation of NMK using acidification with H3PO4, to generate diazomethane for the Pd(OAc)2-catalyzed cyclopropanation of a 1,1-disubstituted alkene has been described by Markus Baenziger (31th International Conference, Organic Process Research and Development, Sep. 29-Oct. 1, 2014, Cologne, Germany).
WO 2015059290 discloses an efficient Pd(acac)2-catalyzed cyclopropanation of a terminally mono-substituted alkene producing diazomethane directly (without nitrogen sparging) in a biphasic reaction mixture consisting of catalyst, substrate, aqueous base and NMK. As stated in Example 7, NMK was prepared as described in WO 2013110932, using H3PO4 for acidification.
When investigating this route for the purpose of assessing its potential as an industrially scalable process, applicant found however, that generating NMK (and by extension, any N-alkyl-N-nitroso compound) using a tribasic acid such as H3PO4, decomposing it to form DAM in-situ without purification or isolation of either NMK or DAM, and reacting the DAM with an alkene substrate to cyclopropanate that substrate, resulted in a poorly reproducible reaction.
Applicant believes—without intending to be bound by any particular theory—the poor reproducibility may have as its cause, the generation of high levels of nitrous gases during NMK formation, which could contaminate both the NMK and the DAM, and poison the catalyst used in the cyclopropanation step.
In addition to this empirical observation, the relatively high price of H3PO4, sustainability issues related to future supply of limited phosphorus resources, and generation of phosphorus waste from the reaction, particularly when using stoichiometric amounts of H3PO4, led the applicant to conclude that the use of a tri-basic acid and in particular H3PO4, contrary to suggestions in the prior art, was not a viable, industrially scalable route.
There remains a need to address the deficiencies in the prior art and to provide a method of cyclopropanating alkene functionality on a substrate that is safe, cost effective, and can reliably produce industrial quantities of product in high yields.